Autoimmune diseases refer to phenomena that the immune system of an organism treats some of the organism's own tissues as “foreign objects” and attacks them. Normally, such diseases can be alleviated by hindering the response of T cells and B cells of the organism to its own tissues. These early immune reactions are prompted by the binding of antigens to MHC molecules and are performed by T cells. The autoimmune diseases mean that the organism's own tissues and proteins are treated as “self-antigens” and are attacked by the organism's immune system. Taking multiple sclerosis—a disease caused by attack of the immune system on the myelin sheath that isolates and protects nerves—for example, when it progresses to an extent that the myelin sheath is lost, neurons and motor nerves will lose their function. Other diseases, such as systemic lupus erythematosus, rheumatoid arthritis, autoimmune hemolytic anemia, also belong to this kind of diseases.
Many drugs have been developed for the treatment of autoimmune diseases, including multiple sclerosis. Glatiramer acetate (also known as copolymer-1, GA) is a mixture of polymers having different molecular weights produced by peptide bond polymerization of alanine, glutamic acid, lysine and tyrosine. The molar ratio of the four amino acids in this mixture is about 0.392 to 0.462:0.129 to 0.153:0.300 to 0.374:0.086 to 0.100 (Ala:Glu:Lys:Tyr), and the average molecular weight of the copolymer in the mixture is about 5,000 to 9,000 daltons. Glatiramer acetate is used for treating patients suffering from intermittent recurrent multiple sclerosis, and for reducing the frequency of recurrence.
Several existing patents (U.S. Pat. No. 5,800,808, CN1310673C, etc.) describe in detail the preparation method, including reacting the protected polymer with 33% of hydrobromic acid in acetic acid. This deprotecting reaction removes the γ benzyl protective group from the 5-carboxylate ester of the glutamic acid residue and cleaves the polymer into smaller polymers to form a trifluoroacetyl polypeptide. The time required for obtaining a proper average molecular weight of GA between 5,000 and 9,000 daltons depends on the reaction temperature and the molecular weight pattern of the protected glatiramer acetate. The deprotection occurs at a temperature between 20° C. and 28° C.
CN101166754B further describes a method, wherein the protected polymer is synthesized, and then it is deprotected with a solution of hydrobromic acid in acetic acid which contains less than 0.5% of free bromine and less than 1000 ppm of metal ions impurities, such that glatiramer acetate is prepared.
However, in a process of practically optimizing the synthesis method of the polymer, the inventors found that this method is not very sensitive to the impurity content and concentration of the solution of hydrobromic acid in acetic acid. Additionally, the thus obtained product is not very satisfactory, and the purity of the obtained glatiramer acetate sample is below the high purity standard required for pharmaceutical use.